Optically active azole derivative and process for producing the same

ABSTRACT

A method for producing an optically active 2-phenyl-2,3,-dihydroxypropyl azole derivative, which is a useful compound in various fields. An optically active α-hydroxycarboxylic acid derivative represented by general formula (1) is used as a starting material and is allowed to react with an azole acetic acid derivative (2) to produce a new, optically active azole-alkyl ketone derivative (3). Subsequently, a new, optically active azole-methyl alcohol derivative (5) is produced by highly diastereoselective alkylation by an appropriate combination of a protective group and an organometallic reagent (4). Furthermore, the optically active azole-methyl alcohol derivative (5) is selectively deprotected to produce an optically active 2-phenyl-2,3-dihydroxypropyl azole derivative (6)

TECHNICAL FIELD

The present invention relates to a new, simple method for producing anoptically active 2-phenyl-2,3,-dihydroxypropyl azole derivative, whichis an important compound in many fields such as medicines andagricultural chemicals.

BACKGROUND ART

Recently, immunocompromised patients due to infection with, for example,AIDS and patients who have a low immunity due to highly developedmedical treatment or due to an increase in old people have beenincreasing. Unfortunately, these phenomena increase the livelihood offungal infections typified by opportunistic infection. A great deal ofattention in medical fields should be paid to deep-seated fungalinfections such as candidiasis and aspergillosis, because these fungalinfections often cause serious life-threatening problems to, inparticular, patients who have a low immunity. Azole antifungal agentstypified by fluconazole have been widely used as a curative medicine forthese infections. In recent years, however, the emergence of resistantstrains and insufficient basic behavior of the known antifungal agentshave been identified. Therefore, the development of a curative medicinethat is effective for a wider range of strains and is more powerful isdesirable (Iyaku Journal, Vol. 37 (7), PP. 115-119, 2001).

According to a recent tendency in the development of azole antifungalagents, antifungal agents have a more complex molecular structure. Inparticular, a significant technical challenge is how to effectivelyachieve a structure that includes an asymmetric carbon bonded to anazole methyl group and an adjoining asymmetric carbon (J. Med. Chem.,Vol. 41, PP. 1869-1882, 1998). In terms of industrial production, astable method for producing an antifungal agent inexpensively has notbeen established so far.

The known processing technology will now be described.

In order to produce the adjoining asymmetric portion, an α-hydroxyphenylketone derivative is generally used as the intermediate and the ketonegroup is subjected to diastereoselective carbon-increasing epoxidation(Chem. Pharm. Bull., Vol. 41 (6), PP. 1035-1042, 1993). Unfortunately,in terms of industrial production, the known method has the followingserious disadvantages: (1) The diastereoselectivity in the method is aslow as about 4:1. (2) The yield in the isolation of the desired isomeris low. (3) The isolation and the purification require very complexsteps. (4) The method causes racemization under some reactionconditions. In addition, a method for producing the α-hydroxyphenylketone derivative also includes complex steps (Bioorg. Med. Chem. Lett.,Vol. 1 (7), PP. 349-352, 1991), and requires an expensive reactionreagent such as an asymmetric catalyst (Tetrahedron Letters, Vol. 37(36), PP. 6531-6534, 1996). Thus, the known method is not a satisfactorymethod in terms of industrial production. Recently, a new, improvedmethod has been reported in which L-alanine is used as the startingmaterial (U.S. Pat. No. 6,300,522). According to this method, however,the fundamental problem is still not solved, because the method alsouses an α-hydroxyphenyl ketone derivative as the intermediate.Therefore, the method is still not a satisfactory method in terms ofindustrial production.

As described above, despite the demand for the development of a new,more useful azole antifungal agent, in terms of industrial production, astable method for producing an antifungal agent inexpensively has notbeen established in the known processing technology, because the azoleantifungal agent is an optically active compound having two asymmetriccarbons. Accordingly, the prompt development of a new, more effectivemethod is desirable regarding the intermediate compound.

DISCLOSURE OF INVENTION

It is an object of the present invention to provide a method forproducing an optically active 2-phenyl-2,3,-dihydroxypropyl azolederivative, which is a useful compound in the field of medicines andagricultural chemicals, and is, in particular, a significantly importantintermediate in the step of producing an optically active azoleantifungal agent. According to the method of the present invention, interms of industrial production, the derivative can be producedinexpensively and stably by simple steps. It is an object of the presentinvention to provide new intermediates produced in some steps in themethod.

As a result of intensive study to achieve the object, the presentinventors have found that it is possible to produce a new, opticallyactive azole-alkyl ketone derivative that is a significantly importantintermediate of medicines and agricultural chemicals by using anoptically active α-hydroxycarboxylic acid derivative as the startingmaterial and by allowing the material to react with an azole acetic acidderivative. The present inventors have also found a highlydiastereoselective reaction in the alkylation of the new, opticallyactive azole-alkyl ketone derivative to produce a new, optically activeazole-methyl alcohol derivative that is a significantly importantintermediate of medicines and agricultural chemicals. According to thediastereoselective reaction, anti or syn configuration can bearbitrarily controlled depending on the selection of the protectivegroup and the reaction conditions. Furthermore, the present inventorshave found a new route for producing an optically active2-phenyl-2,3-dihydroxypropyl azole derivative, which is a significantlyimportant intermediate of medicines and agricultural chemicals, byselectively deprotecting the new optically active azole-methyl alcoholderivative. According to this reaction, a compound having the desiredconfiguration can be selectively produced with high optical puritywithout racemization. In particular, the present inventors have foundthe following method: An inexpensive lactic acid derivative is used asthe optically active α-hydroxycarboxylic acid derivative. A silyl groupis used as the protective group to produce a new, optically activesilyloxy-azole-alkyl ketone derivative, which is an intermediate. Theintermediate is then subjected to alkylation with significantly high synselectivity to produce a new, optically active silyloxy-azole-methylalcohol derivative. The optically active silyloxy-azole-methyl alcoholderivative is a significantly important intermediate to produce anoptically active azole antifungal agent. Accordingly, a2-phenyl-2,3-dihydroxypropyl azole derivative having the desiredconfiguration can be produced with high optical purity. According tothis method, the 2-phenyl-2,3-dihydroxypropyl azole derivative, which isa significantly important intermediate to produce the optically activeazole antifungal agent, can be produced inexpensively and stably bysimple steps, in terms of industrial production. The present inventionis based on this fact found by the inventors.

The present invention includes following Items [1] to [14].

-   [1] A method for producing an optically active    2-phenyl-2,3-dihydroxypropyl azole derivative represented by general    formula (6):

(wherein R1 represents a substituted or unsubstituted alkyl group, asubstituted or unsubstituted aralkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted heterocyclicgroup; each of R5 and R6 independently represents a halogen atom, analkyloxycarbonyl group, an aryloxycarbonyl group, a substituted orunsubstituted amino group, a substituted or unsubstituted amido group, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedalkyloxy group, a substituted or unsubstituted aralkyl group, asubstituted or unsubstituted aralkyloxy group, a substituted orunsubstituted phenyl group, a substituted or unsubstituted phenoxygroup, a substituted or unsubstituted heterocyclic group, or asubstituted or unsubstituted heterocyclicoxy group; symbol * representsan asymmetric carbon having an R configuration or an S configuration;and Y represents a carbon atom or a nitrogen atom) includes the steps ofallowing an optically active α-hydroxycarboxylic acid derivativerepresented by general formula (1):

(wherein R1 and symbol * are as defined above; R2 represents an etherprotective group, an acetal protective group, or a silyl protectivegroup, which is a protective group for a hydroxyl group; R3 represents ahydroxyl group, a halogen atom, a substituted or unsubstituted acylgroup, a substituted or unsubstituted carbonate group, a substituted orunsubstituted alkyloxy group, a substituted or unsubstituted aralkyloxygroup, a substituted or unsubstituted phenoxy group, or a substituted orunsubstituted amino group) to react with an azole acetic acid derivativerepresented by general formula (2):

(wherein R4 represents a hydrogen atom, a substituted or unsubstitutedalkyl group, an alkali metal, or an alkaline earth metal salt; and Y isas defined above) under a basic condition to produce an azole-methylketone derivative represented by general formula (3):

(wherein R1, R2, symbol *, and Y are as defined above); allowing theoptically active azole-methyl ketone derivative represented by generalformula (3) to diastereoselectively react with a phenyl metallic reagentrepresented by general formula (4):

(wherein R5 and R6 are as defined above; A represents Li, MgX, ZnX,TiX₃, Ti(OR7)₃, CuX, or CuLi, {wherein X represents a halogen atom, andR7 represents a substituted or unsubstituted alkyl group}) to produce anoptically active azole-methyl alcohol derivative represented by generalformula (5):

(wherein R1, R2, R5, R6, symbol *, and Y are as defined above); andselectively deprotecting the protective group R2 for a hydroxyl group ofthe optically active azole-methyl alcohol derivative represented bygeneral formula (5).

-   [2] A method for producing an azole-methyl ketone derivative    represented by general formula (3) (wherein R1, R2, Y, and symbol *    are as defined above) includes allowing an α-hydroxycarboxylic acid    derivative represented by general formula (1) (wherein R1, R2, R3,    and symbol * are as defined above) to react with an azole acetic    acid derivative represented by general formula (2) (wherein R4 and Y    are as defined above) under a basic condition.-   [3] A method for producing an optically active azole-methyl alcohol    derivative represented by general formula (5) (wherein R1, R2, R5,    R6, Y, and symbol * are as defined above) includes allowing an    optically active azole-methyl ketone derivative represented by    general formula (3) (wherein R1, R2, Y, and symbol * are as defined    above) to diastereoselectively react with a phenyl metallic reagent    represented by general formula (4) (wherein R5, R6, A, X, and R7 are    as defined above).-   [4] A method for producing an optically active azole-methyl alcohol    derivative represented by general formula (5) (wherein R1, R2, R5,    R6, Y, and symbol * are as defined above) includes allowing an    optically active azole-methyl ketone derivative represented by    general formula (3) (wherein R1, R2, Y, and symbol * are as defined    above) to anti-selectively react with a phenyl metallic reagent    represented by general formula (4) (wherein R5, R6, A, X, and R7 are    as defined above).-   [5] A method for producing an optically active azole-methyl alcohol    derivative represented by general formula (5) (wherein R1, R2, R5,    R6, Y, and symbol * are as defined above) includes allowing an    optically active azole-methyl ketone derivative represented by    general formula (3) (wherein R1, R2, Y, and symbol * are as defined    above) to syn-selectively react with a phenyl metallic reagent    represented by general formula (4) (wherein R5, R6, A, X, and R7 are    as defined above).-   [6] A method for producing an optically active    2-phenyl-2,3-dihydroxypropyl azole derivative represented by general    formula (6) (wherein R1, R5, R6, Y, and symbol * are as defined    above) includes selectively deprotecting the protective group R2 for    a hydroxyl group of an optically active azole-methyl alcohol    derivative represented by general formula (5) (wherein R1, R2, R5,    R6, Y, and symbol * are as defined above).-   [7] The method according to any one of Item [1] to Item [6] wherein    R1 is a methyl group, and each of R5 and R6 is a fluorine or    chlorine atom.-   [8] An optically active azole-methyl ketone represented by general    formula (3) (wherein R1, R2, Y, and symbol * are as defined above).-   [9] The optically active azole-methyl ketone according to Item [8],    wherein R1 is a methyl group.-   [10] The optically active azole-methyl ketone according to Item [9],    wherein R2 is a silyl protective group.-   [11] An optically active azole-methyl alcohol derivative represented    by general formula (5) (wherein R1, R5, R6, Y, and symbol * are as    defined above), wherein R2 is a silyl protective group.-   [12] The optically active azole-methyl alcohol derivative according    to Item [11], wherein R1 is a methyl group.-   [13] The optically active azole-methyl alcohol derivative according    to Item [12], wherein each of R5 and R6 is a halogen atom.-   [14] The optically active azole-methyl alcohol derivative according    to Item [13], wherein Y is a nitrogen atom.

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds of the present invention will now be described in detail.

According to the present invention, “a substituted or unsubstitutedalkyl group” represents an alkyl group in which any position of thealkyl group may be substituted. Examples of the alkyl group includemethyl, ethyl, isopropyl, tert-butyl, pentyl, hexyl, octyl, decyl, andallyl groups. Examples of the substituent include; hydroxyl group;alkoxy groups such as methoxy, benzyloxy, and methoxyethoxy groups; aphenoxy group; a nitro group; an amino group; an amido group; a carboxylgroup; alkoxycarbonyl groups; a phenoxycarbonyl group; and halogen atomssuch as fluorine, chlorine, bromine, and iodine atoms.

According to the present invention, “a substituted or unsubstitutedaralkyl group” represents an aralkyl group in which any position of thearalkyl group may be substituted. Examples of the aralkyl group includebenzyl, naphthylmethyl, phenylethyl, and 9-fluorenylmethyl groups.Examples of the substituent include alkyl groups such as methyl,tert-butyl, and benzyl groups; cycloalkyl groups such as cyclopropane,cyclopentane, and cyclohexane; a phenyl group; hydroxyl group; alkoxygroups such as methoxy, benzyloxy, and methoxyethoxy groups; a phenoxygroup; a nitro group; an amino group; an amido group; a carboxyl group;alkoxycarbonyl groups; a phenoxycarbonyl group; and halogen atoms suchas fluorine, chlorine, bromine, and iodine atoms.

According to the present invention, “a substituted or unsubstituted arylgroup” represents an aryl group in which any position of the aryl groupmay be substituted. Examples of the aryl group include phenyl, naphthyl,anthracenyl, fluorenyl, and phenanthryl groups. Examples of thesubstituent include alkyl groups such as methyl, tert-butyl, and benzylgroups; cycloalkyl groups such as cyclopropane, cyclopentane, andcyclohexane; a phenyl group; hydroxyl group; alkoxy groups such asmethoxy, benzyloxy, and methoxyethoxy groups; a phenoxy group; a nitrogroup; an amino group; an amido group; a carboxyl group; alkoxycarbonylgroups; a phenoxycarbonyl group; and halogen atoms such as fluorine,chlorine, bromine, and iodine atoms.

According to the present invention, “a substituted or unsubstitutedheterocyclic group” represents a heterocyclic group in which anyposition of the heterocyclic group having a heteroatom such as oxygen,nitrogen, and sulfur atoms may be substituted. Examples of theheterocyclic group include tetrahydropyranyl, tetrahydrofuranyl,tetrahydrothienyl, piperidyl, morpholinyl, piperazinyl, pyrrolyl, furyl,thienyl, pyridyl, furfuryl, thenyl, pyridylmethyl, pyrimidyl, pyrazyl,imidazolyl, imidazolylmethyl, indolyl, indolylmethyl, isoquinolyl,quinolyl, and thiazolyl groups. Examples of the substituent includealkyl groups such as methyl, tert-butyl, and benzyl groups; cycloalkylgroups such as cyclopropane, cyclopentane, and cyclohexane; a phenylgroup; hydroxyl group; alkoxy groups such as methoxy, benzyloxy, andmethoxyethoxy groups; a phenoxy group; a nitro group; an amino group; anamido group; a carboxyl group; alkoxycarbonyl groups; a phenoxycarbonylgroup; and halogen atoms such as fluorine, chlorine, bromine, and iodineatoms.

According to the present invention, “an ether protective group which isa protective group for a hydroxyl group” represents a protective groupthat protects the hydroxyl group, and the protective group having anether bond. Examples of the protective group include methyl, ethyl,tert-butyl, octyl, allyl, benzyl, p-methoxybenzyl, fluorenyl, trityl,and benzhydryl groups.

According to the present invention, “an acetal protective group”represents a protective group that protects the hydroxyl group, and theprotective group having an acetal bond. Examples of the protective groupinclude methoxymethyl, ethoxyethyl, methoxyethoxymethyl,tetrahydropyranyl, and tetrahydrofuranyl groups.

According to the present invention, “a silyl protective group”represents a protective group that protects the hydroxyl group, and theprotective group having a silyloxy bond. Examples of the protectivegroup include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl,and tert-butyldiphenylsilyl groups.

According to the present invention, examples of “a halogen atom” includefluorine, chlorine, bromine, and iodine atoms.

According to the present invention, “a substituted or unsubstituted acylgroup” represents an acyl group in which any position of the acyl groupmay be substituted. Examples of the acyl group include formyl, acetyl,propionyl, pivaloyl, and benzoyl groups. Examples of the substituentinclude alkyl groups such as methyl, tert-butyl, and benzyl groups;cycloalkyl groups such as cyclopropane, cyclopentane, and cyclohexane; aphenyl group; hydroxyl group; alkoxy groups such as methoxy, benzyloxy,and methoxyethoxy groups; a phenoxy group; a nitro group; an aminogroup; an amido group; a carboxyl group; alkoxycarbonyl groups; aphenoxycarbonyl group; and halogen atoms such as fluorine, chlorine,bromine, and iodine atoms.

According to the present invention, “a substituted or unsubstitutedcarbonate group” represents a carbonate group in which any position ofthe carbonate group may be substituted. Examples of the carbonate groupinclude methyl carbonate, ethyl carbonate, isopropyl carbonate, andbenzyl carbonate groups. Examples of the substituent include alkylgroups such as methyl, tert-butyl, and benzyl groups; cycloalkyl groupssuch as cyclopropane, cyclopentane, and cyclohexane; a phenyl group;hydroxyl group; alkoxy groups such as methoxy, benzyloxy, andmethoxyethoxy groups; a phenoxy group; a nitro group; an amino group; anamido group; a carboxyl group; alkoxycarbonyl groups; a phenoxycarbonylgroup; and halogen atoms such as fluorine, chlorine, bromine, and iodineatoms.

According to the present invention, “a substituted or unsubstitutedalkyloxy group” represents an alkyloxy group in which any position ofthe alkyloxy group may be substituted. Examples of the alkyloxy groupinclude methoxy, ethoxy, isopropoxy, tert-butoxy, pentyloxy, hexyloxy,octyloxy, decyloxy, and allyloxy groups. Examples of the substituentinclude hydroxyl group; alkoxy groups such as methoxy, benzyloxy, andmethoxyethoxy groups; a phenoxy group; a nitro group; an amino group; anamido group; a carboxyl group; alkoxycarbonyl groups; a phenoxycarbonylgroup; and halogen atoms such as fluorine, chlorine, bromine, and iodineatoms.

According to the present invention, “a substituted or unsubstitutedaralkyloxy group” represents an aralkyloxy group in which any positionof the aralkyloxy group may be substituted. Examples of the aralkyloxygroup include benzyloxy, naphthylmethyloxy, phenylethyloxy, and9-fluorenylmethyloxy groups. Examples of the substituent include alkylgroups such as methyl, tert-butyl, and benzyl groups; cycloalkyl groupssuch as cyclopropane, cyclopentane, and cyclohexane; a phenyl group;hydroxyl group, alkoxy groups such as methoxy, benzyloxy, andmethoxyethoxy groups; a phenoxy group; a nitro group; an amino group; anamido group; a carboxyl group; alkoxycarbonyl groups; a phenoxycarbonylgroup; and halogen atoms such as fluorine, chlorine, bromine, and iodineatoms.

According to the present invention, “a substituted or unsubstitutedphenoxy group” represents a phenoxy group in which any position of thephenoxy group may be substituted. Examples of the substituent includealkyl groups such as methyl, tert-butyl, and benzyl groups; cycloalkylgroups such as cyclopropane, cyclopentane, and cyclohexane; a phenylgroup; hydroxyl group; alkoxy groups such as methoxy, benzyloxy, andmethoxyethoxy groups; a phenoxy group; a nitro group; an amino group; anamido group; a carboxyl group; alkoxycarbonyl groups; a phenoxycarbonylgroup; and halogen atoms such as fluorine, chlorine, bromine, and iodineatoms.

According to the present invention, “a substituted or unsubstitutedamino group” represents an amino group in which any position of theamino group may be substituted. Examples of the substituent includealkyl groups such as methyl, tert-butyl, and benzyl groups; cycloalkylgroups such as cyclopropane, cyclopentane, and cyclohexane; and a phenylgroup.

According to the present invention, examples of “an alkali metal”include lithium, sodium, potassium, rubidium, and cesium.

According to the present invention, “an alkaline earth metal salt”represents a salt of, for example, magnesium, calcium, strontium,barium, or beryllium. Examples of the alkaline earth metal salt includemagnesium halides, magnesium alkoxides, calcium halides, calciumalkoxides, strontium halides, barium halides, and beryllium halides. Inmore detail, examples of the alkaline earth metal salt include magnesiumsalts such as —MgCl, —MgBr, —MgOMe, and —MgOEt; calcium salts such as—CaCl, —CaBr, —CaOMe, and —CaOEt; and barium salts such as —BaCl, —BaBr,—BaOMe, and —BaOEt. Two molecules of an azole acetic acid derivative mayform a single alkaline earth metal salt.

According to the present invention, examples of “an alkyloxycarbonylgroup” include methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonylgroups.

According to the present invention, examples of “an aryloxycarbonylgroup” include phenoxycarbonyl and naphthyloxycarbonyl groups.

According to the present invention, “a substituted or unsubstitutedamido group” represents an amido group in which any position of theamido group may be substituted. Examples of the substituent includealkyl groups such as methyl, tert-butyl, and benzyl groups; cycloalkylgroups such as cyclopropane, cyclopentane, and cyclohexane; and a phenylgroup.

According to the present invention, “a substituted or unsubstitutedheterocyclicoxy group” represents a heterocyclicoxy group in which anyposition of the heterocyclicoxy group may be substituted. Examples ofthe heterocyclicoxy group include tetrahydropyranyloxy,tetrahydrofuranyloxy, tetrahydrothienyloxy, piperidyloxy,morpholinyloxy, piperazinyloxy, pyrrolyloxy, furyloxy, thienyloxy,pyridyloxy, furfuryloxy, thenyloxy, pyridylmethyloxy, pyrimidyloxy,pyrazyloxy, imidazolyloxy, imidazolylmethyloxy, indolyloxy,indolylmethyloxy, isoquinolyloxy, quinolyloxy, and thiazolyloxy groups.Examples of the substituent include alkyl groups such as methyl,tert-butyl, and benzyl groups; cycloalkyl groups such as cyclopropane,cyclopentane, and cyclohexane; a phenyl group; hydroxyl group; alkoxygroups such as methoxy, benzyloxy, and methoxyethoxy groups; a phenoxygroup; a nitro group; an amino group; an amido group; a carboxyl group;alkoxycarbonyl groups; a phenoxycarbonyl group; and halogen atoms suchas fluorine, chlorine, bromine, and iodine atoms.

According to the present invention, “allowing the compound representedby general formula (3) to diastereoselectively react with the reagentrepresented by general formula (4) to produce the compound representedby general formula (5)” means to selectively produce a new asymmetriccarbon adjoining an asymmetric carbon in general formula (3). The term“anti-selectively” has the following meaning. In a plane on which acarbon chain is disposed in a zigzag, a hydroxyl group is produced atthe opposite side of the R2O-group bonded to the optically active carbonatom. The term “syn-selectively” has the following meaning. In a planeon which a carbon chain is disposed in a zigzag, a hydroxyl group isproduced at the same side of the R2O-group bonded to the opticallyactive carbon atom. In other words, the selectivity represented by“anti-selectively” is the diastereoselectivity represented by generalformula (7).

As shown in general formula (7), an (S)-enantiomer produces an (S,R)-diastereomer, and an (R)-enantiomer produces an (R, S)-diastereomer.

The selectivity represented by “syn-selectively” is thediastereoselectivity represented by general formula (8).

As shown in general formula (8), the (S)-enantiomer produces an (S,S)-diastereomer, and the (R)-enantiomer produces an (R, R)-diastereomer.

Tables 1 to 10 show examples of the compounds represented by generalformulae (3), (5), (6), (8), (9), and (10). The compounds of the presentinvention are not limited to the following compounds.

TABLE 1 General formula (3)

Configuration Compound at 3rd number position R1 R2 Y R101 R CH₃— CH₃— NR102 R (CH₃)₂CH— CH₃— N R103 R PhCH₂— CH₃— N R104 R (CH3)₃C— CH₃— C R105R PhCH₂OCH₂— CH₃— N R106 R CH₃OC(O)CH₂— CH₃— N R107 R ClCH₂— CH₃— N R108R H₂NC(O)CH₂CH₂— CH₃— C R109 R

CH₃— N R110 R

CH₃— N R111 R CH₃— PhCH₂— N R112 R (CH₃)₂CH— PhCH₂— N R113 R PhCH₂—PhCH₂— C R114 R (CH3)₃C— PhCH₂— N R115 R PhCH₂OCH₂— PhCH₂— N R116 RCH₃OC(O)CH₂— PhCH₂— C R117 R ClCH₂— PhCH₂— N R118 R H₂NC(O)CH₂CH₂—PhCH₂— N R119 R

PhCH₂— N R120 R

PhCH₂— N R121 R CH₃— CH₃OCH₂— N R122 R (CH₃)₂CH— CH₃OCH₂— C R123 RPhCH₂— CH₃OCH₂— N R124 R (CH3)₃C— CH₃OCH₂— N R125 R PhCH₂OCH₂— CH₃OCH₂—C R126 R CH₃—

N R127 R CH₃— Ph3C— N R128 R CH₃— t-BuPh2Si— N R129 R CH₃— t-BuMe2Si— NR130 R CH₃— (CH₃)₃Si— N R131 R CH₃— Et₃Si— N

TABLE 2 General formula (3)

Configuration Compound at 3rd number position R1 R2 Y S101 S CH₃— CH₃— NS102 S (CH₃)₂CH— CH₃— N S103 S PhCH₂— CH₃— N S104 S (CH3)₃C— CH₃— C S105S PhCH₂OCH₂— CH₃— N S106 S CH₃OC(O)CH₂— CH₃— N S107 S ClCH₂— CH₃— N S108S H₂NC(O)CH₂CH₂— CH₃— C S109 S

CH₃— N S110 S

CH₃— N S111 S CH₃— PhCH₂— N S112 S (CH₃)₂CH— PhCH₂— N S113 S PhCH₂—PhCH₂— C S114 S (CH3)₃C— PhCH₂— N S115 S PhCH₂OCH₂— PhCH₂— N S116 SCH₃OC(O)CH₂— PhCH₂— C S117 S ClCH₂— PhCH₂— N S118 S H₂NC(O)CH₂CH₂—PhCH₂— N S119 S

PhCH₂— N S120 S

PhCH₂— N S121 S CH₃— CH₃OCH₂— N S122 S (CH₃)₂CH— CH₃OCH₂— C S123 SPhCH₂— CH₃OCH₂— N S124 S (CH3)₃C— CH₃OCH₂— N S125 S PhCH₂OCH₂— CH₃OCH₂—C S126 S CH₃—

N S127 S CH₃— Ph3C— N R128 S CH₃— t-BuPh2Si— N R129 S CH₃— t-BuMe2Si— NR130 S CH₃— (CH₃)₃Si— N R131 S CH₃— Et₃Si— N

TABLE 3 General formula (5)

Compound Configuration number 2nd 3rd R1 R2

Y RR131 R R PhCH₂— CH₃—

C RR132 R R CH₃— PhCH₂—

N RR133 R R CH₃—

N RR134 R R CH₃—

C RR135 R R CH₃— CH₃OCH₂—

N RR136 R R CH₃— (CH₃)₃Si—

N RR137 R R CH₃—

N RR138 R R CH₃— Ph3C—

N RR139 R R CH₃— t-BuPh2Si—

N RR140 R R CH₃— PhCH₂—

N RR141 R R CH₃—

N RR142 R R CH₃— Et3Si—

N RR143 R R CH₃— t-BuMe2Si-

N RR144 R R CH₃— t-BuMe2Si-

C

TABLE 4 General formula (5)

Compound Configuration number 2nd 3rd R1 R2

Y SR131 S R PhCH₂— CH₃—

C SR132 S R CH₃— PhCH₂—

N SR133 S R CH₃—

N SR134 S R CH₃—

C SR135 S R CH₃— CH₃OCH₂—

N SR136 S R CH₃— (CH₃)₃Si—

N SR137 S R CH₃—

N SR138 S R CH₃— Ph3C—

N SR139 S R CH₃— t-BuPh2Si—

N SR140 S R CH₃— PhCH₂—

N SR141 S R CH₃—

N

TABLE 5 General formula (5)

Compound Configuration number 2nd 3rd R1 R2

Y SS131 S S PhCH₂— CH₃—

C SS132 S S CH₃— PhCH₂—

N SS133 S S CH₃—

N SS134 S S CH₃—

C SS135 S S CH₃— CH₃OCH₂—

N SS136 S S CH₃— (CH₃)₃Si—

N SS137 S S CH₃—

N SS138 S S CH₃— Ph3C—

N SS139 S S CH₃— t-BuPh2Si—

N SS140 S S CH₃— PhCH₂—

N SS141 S S CH₃—

N

TABLE 6 General formula (5)

Compound Configuration number 2nd 3rd R1 R2

Y RS131 R S PhCH₂— CH₃—

C RS132 R S CH₃— PhCH₂—

N RS133 R S CH₃—

N RS134 R S CH₃—

C RS135 R S CH₃— CH₃OCH₂—

N RS136 R S CH₃— (CH₃)₃Si—

N RS137 R S CH₃—

N RS138 R S CH₃— Ph3C—

N RS139 R S CH₃— t-BuPh2Si—

N RS140 R S CH₃— PhCH₂—

N RS141 R R CH₃—

N

TABLE 7 General formula (6)

Compound Configuration number 2nd 3rd R1

Y RR142 R R CH₃—

C RR143 R R CH₃—

N RR144 R R CH3CH2—

N RR145 R R (CH₃)₂CH—

C RR146 R R (CH₃)₂CH—

N RR147 R R (CH₃)₃C—

N RR148 R R CH₃—

N RR149 R R CH₃—

C RR150 R R PhCH₂—

N RR151 R R CH₃—

N RR152 R R CH₃—

C

TABLE 8 General formula (6)

Compound Configuration number 2nd 3rd R1

Y SR142 S R CH₃—

C SR143 S R CH₃—

N SR144 S R CH3CH2—

N SR145 S R (CH₃)₂CH—

C SR146 S R (CH₃)₂CH—

N SR147 S R (CH₃)₃C—

N SR148 S R CH₃—

N SR149 S R CH₃—

C SR150 S R PhCH₂—

N SR151 S R CH₃—

N SR152 S R CH₃—

C

TABLE 9 General formula (6)

Compound Configuration number 2nd 3rd R1

Y SS142 S S CH₃—

C SS143 S S CH₃—

N SS144 S S CH3CH2—

N SS145 S S (CH₃)₂CH—

C SS146 S S (CH₃)₂CH—

N SS147 S S (CH₃)₃C—

N SS148 S S CH₃—

N SS149 S S CH₃—

C SS150 S S PhCH₂—

N SS151 S S CH₃—

N SS152 S S CH₃—

C

TABLE 10 General formula (6)

Compound Configuration number 2nd 3rd R1

Y RS142 R S CH₃—

C RS143 R S CH₃—

N RS144 R S CH3CH2—

N RS145 R S (CH₃)₂CH—

C RS146 R S (CH₃)₂CH—

N RS147 R S (CH₃)₃C—

N RS148 R S CH₃—

N RS149 R S CH₃—

C RS150 R S PhCH₂—

N RS151 R S CH₃—

N RS152 R S CH₃—

C

A typical method of the present invention will now be described.

[1] A method for producing an optically active azole-methyl ketonederivative represented by general formula (3) will now be described.

An azole-methyl ketone derivative represented by general formula (3) isproduced by allowing an optically active α-alkoxycarboxylic acidderivative represented by general formula (1) to react with an azoleacetic acid derivative represented by general formula (2) under a basiccondition. According to this reaction, a decarboxylation proceeds afteror during a carbon-carbon bonding reaction, thereby effectivelyintroducing an azole methyl group. Although an optically activesubstance is used as the starting material, this reaction hardlydecreases the optical purity of the resultant product.

The base used for the above reaction is not limited. Examples of thebase include inorganic bases such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,and sodium hydrogencarbonate. Examples of the base include organic aminebases such as triethylamine, pyridine, and 1,8-diazabicycloundecene.Examples of the base include alkoxides such as sodium methoxide, sodiumethoxide, and potassium tert-butoxide. Examples of the base includemetal hydrides such as lithium hydride and sodium hydride. Examples ofthe base include organometallic bases such as alkyl lithium and Grignardreagents, e.g., in particular, n-butyllithium, ethyl magnesium bromide,n-butyl magnesium chloride, and tert-butyl magnesium chloride. Examplesof the base include metallic amide base such as sodium amide, lithiumamide, and magnesium amide. In particular, examples of the metallicamide base include lithium diisopropylamide and magnesium halidedialkylamide, e.g., magnesium chloride diisopropylamide. These bases maybe used alone or in combination of two or more.

Any solvent may be used as long as the reaction is not inhibited.Examples of the solvent include water; alcohols such as methanol,ethanol, and butanol; hydrocarbons such as hexane, toluene, and xylenes;esters such as ethyl acetate and butyl acetate; ethers such as diethylether, dioxane, ethylene glycol dimethyl ether, and tetrahydrofuran;halogenated hydrocarbons such as chloroform and dichloromethane;acetonitrile; dimethylformamide; dimethylsulfoxide; anddimethylimidazolidinone. These solvents may be used alone or incombination of two or more at any mixing ratio. The reaction temperatureis generally in the range of −78° C. to the boiling point of the solventused, and preferably, −20° C. to the boiling point of the solvent.Although the reaction time is not limited, the reaction time isgenerally in the range of several minutes to 24 hours, and preferably,30 minutes to 6 hours.

[2] A method for producing an optically active azole-methyl alcoholderivative represented by general formula (5) will now be described.

An optically active azole-methyl alcohol derivative represented bygeneral formula (5) is produced by allowing an optically activeazole-methyl ketone derivative represented by general formula (3) toreact with a phenyl metallic reagent represented by general formula (4).In this reaction, the diastereoselectivity depends on the combination ofa protective group R2 for a hydroxyl group and a metal represented by A.Anti or syn configuration can be arbitrarily synthesized depending onthe appropriate selection of the protective group and the metal.

In short, in this reaction, an organometallic reagent is allowed toreact with the optically active azole-methyl ketone derivative accordingto a chelation model wherein the configuration of the oxygen atom in theR2O-group and the carbonyl group relating to the reaction is determinedby the coordination of the metal. Thus, a desired product can beproduced with high anti diastereoselectivity. In more detail, a compoundhaving an S configuration selectively produces a compound having an S—Rconfiguration, and a compound having an R configuration selectivelyproduces a compound having an R—S configuration. In particular, forexample, a benzyl or methoxymethyl group is used as the protective groupand a Grignard reagent is used as the organometallic reagent. In thiscase, the desired reaction proceeds with high anti selectivity (>6:1).

On the other hand, a desired product can be produced with high synselectivity by using a bulky protective group R2 for the hydroxyl group,and an appropriate metallic reagent. In more detail, a compound havingan S configuration selectively produces a compound having an S—Sconfiguration, and a compound having a R configuration selectivelyproduces a compound having an R—R configuration with high synselectivity (>4:1). The use of a silyl protective group allows thedesired reaction to take place with significantly high syn selectivity(>20:1). Examples of the silyl protective group include trimethylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and triethylsilylgroups.

Although an optically active substance is used as the starting material,this reaction hardly decreases the optical purity of the resultantproduct. Examples of a phenyl metallic compound include phenyl-lithiumderivatives, phenyl-magnesium derivatives, phenyl-zinc derivatives,phenyl-titanium derivatives, phenyl-copper derivatives, andphenyl-copper-lithium derivatives. Additives may be added to thereaction system in order to change the diastereoselectivity and toimprove the yield. Examples of the additives include Lewis acids andquaternary ammonium salts. In more detail, examples of the additivesinclude CeCl₃, MgBr₂, MgCl₂, ZnCl₂, ZnBr₂, CuCl₂, TiCl₄, BF₃, AlCl₃,SnCl₄, and SnCl₂.

Any solvent may be used as long as the reaction is not inhibited.Examples of the solvent include water; alcohols such as methanol,ethanol, and butanol; hydrocarbons such as hexane, toluene, and xylenes;esters such as ethyl acetate and butyl acetate; ethers such as diethylether, dioxane, ethylene glycol dimethyl ether, and tetrahydrofuran;halogenated hydrocarbons such as chloroform and dichloromethane;acetonitrile; dimethylformamide; dimethylsulfoxide; anddimethylimidazolidinone. These solvents may be used alone or incombination of two or more at any mixing ratio. The reaction temperatureis generally in the range of −78° C. to the boiling point of the solventused, and preferably, −40° C. to room temperature. Although the reactiontime is not limited, the reaction time is generally in the range ofseveral minutes to 24 hours, and preferably, 30 minutes to 6 hours.

[3] A method for producing an optically active2-phenyl-2,3-dihydroxypropyl azole derivative represented by generalformula (6) will now be described.

An optically active 2-phenyl-2,3-dihydroxypropyl azole derivativerepresented by general formula (6) is produced by selectivelydeprotecting the protective group R2 for a hydroxyl group in anoptically active azole-methyl alcohol derivative represented by generalformula (5). The method for deprotecting the hydroxyl group is notlimited as long as the molecular structure other than the deprotectedportion is not changed. An ether protective group is deprotected by acidtreatment using, for example, hydrochloric acid, sulfuric acid,trifluoroacetic acid, p-toluene sulfonic acid, or acetic acid; or bycatalytic hydrogenation using a catalyst such as palladium-carbon. Anacetal protective group is deprotected by acid treatment using, forexample, hydrochloric acid, sulfuric acid, trifluoroacetic acid,p-toluene sulfonic acid, pyridinium p-toluene sulfonic acid, or aceticacid. A silyl protective group is deprotected by acid treatment using,for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid,p-toluene sulfonic acid, pyridinium p-toluene sulfonic acid, or aceticacid; or by fluoride anion treatment using, for example,tetra-n-butyl-ammonium fluoride. Any solvent may be used as long as thereaction is not inhibited. Examples of the solvent include water;alcohols such as methanol, ethanol, and butanol; hydrocarbons such ashexane, toluene, and xylenes; esters such as ethyl acetate and butylacetate; ethers such as diethyl ether, dioxane, ethylene glycol dimethylether, and tetrahydrofuran; halogenated hydrocarbons such as chloroformand dichloromethane; acetonitrile; dimethylformamide; anddimethylsulfoxide. These solvents may be used alone or in combination oftwo or more at any mixing ratio. The reaction temperature is generallyin the range of −20° C. to the boiling point of the solvent used.Although the reaction time is not limited, the reaction time isgenerally in the range of several minutes to 24 hours, and preferably,30 minutes to 6 hours.

The optically active α-hydroxycarboxylic acid derivative represented bygeneral formula (1) is readily and commercially available or can besynthesized by generally known methods. For example, the opticallyactive α-hydroxycarboxylic acid derivative can be synthesized by usinglactic acid (Chem. Pharm. Bull., Vol. 41 (6), PP. 1035-1042, 1993),various amino acids (Synthesis, 1987, P. 479), or an α-halocarboxylicacid derivative (Tetrahedron Lett., 1985, Vol. 26, P. 5257). The azoleacetic acid derivative represented by general formula (2) can be readilysynthesized by known methods (for example, Tetrahedron Lett., 2000, 41(8), 1297). In the present invention, methods for producing somereagents and starting materials are not specifically described. Ingeneral, these reagents and materials are commercially available, andtherefore readily available.

Although examples of the present invention will now be described, thepresent invention is not limited to the following examples.

EXAMPLE 1 Synthesis of(3R)-1-(1H-1,2,4-triazol-1-yl)-3-(triphenylmethyloxy)-2-butanone

Tetrahydrofuran (4 mL) and triethylamine (0.44 g) were added to triazoleacetic acid (0.55 g) and the mixture was stirred at room temperature fortwo hours. Subsequently, methyl (2R)-2-(triphenylmethyloxy) propionate(1.00 g) was mixed with the mixture at room temperature. The resultanthomogeneous mixture is hereinafter referred to as Solution A. A solution(25 mL) of tetrahydrofuran containing tert-butyl magnesium chloride(0.91 M) was heated at 40° C. to 45° C. Solution A was added dropwise tothe solution for one hour. The mixture was then stirred at 40° C. to 45°C. for four hours. The reaction mixture was cooled on ice to 50° C., andsulfuric acid (2 N, 30 mL) was added dropwise to the mixture. Ethylacetate (50 mL) was added to the mixture to extract the target compound.Thus, an organic layer was separated. The organic layer was washed withsaturated sodium bicarbonate (40 mL), and subsequently washed with asaturated saline solution (40 mL). The washed organic layer was driedwith anhydrous sodium sulfate, and was then concentrated. The resultantsubstance was purified by silica gel column chromatography (equivalentto Merck C-300, 15 g, pure chloroform to chloroform:methanol=8:2). Theresultant substance was crystallized with hexane to recover light yellowcrystals of the target compound (0.60 g, 52%).

Melting point: 162° C. (decomposition) ¹H-N.M.R. (270 MHz, CDCl₃):δ=7.84(s, 1H), 7.48(s, 1H), 7.45-7.25(m, 15H), 5.01(d, 1H, J=8.8 Hz),4.40(q, 1H, J=6.9 HZ), 4.07(d, 1H, J=8.8 Hz), and 1.51(d, 3H, J=6.9 Hz)

EXAMPLE 2 Synthesis of(3R)-3-(benzyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone

The target compound (7.6 g, 30%), which was a transparent and colorlesssyrup, was recovered as in Example 1, except methyl (2R)-2-(benzyloxy)propionate (20.0 g) was used instead of methyl(2R)-2-(triphenylmethyloxy) propionate.

¹H-N.M.R. (270 MHz, DMSO-d6): δ=8.44(s, 1H), 7.98(s, 1H), 7.50-7.20(m,5H), 5.55(d, 1H, J=18.6 Hz), 5.43(d, 1H, J=18.6 Hz), 4.61(s, 2H),4.26(q, 1H, J=6.9 Hz), and 1.34(d, 3H, J=6.9 Hz)

EXAMPLE 3 Synthesis of(3S)-3-(benzyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone

The target compound (340 mg, 19%), which was a transparent and colorlesssyrup, was recovered as in Example 1, except benzyl (2S)-2-(benzyloxy)propionate (1.88 g) was used instead of methyl(2R)-2-(triphenylmethyloxy) propionate. The values of the physicalproperties corresponded with those in Example 2.

EXAMPLE 4 Synthesis of(3R)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone

The target compound (1.59 g, 40%), which was a transparent and colorlesssyrup, was recovered as in Example 1, except methyl(2R)-2-(methoxymethyloxy) propionate (2.96 g, 20 mmol) was used insteadof methyl (2R)-2-(triphenylmethyloxy) propionate.

¹H-N.M.R. (270 MHz, CDCl₃) : δ=8.14 (s, 1H), 7.97(s, 1H), 5.36(d, 1H,J=8.8 Hz), 5.22(d, 1H, J=8.8 Hz), 4.73-4.70(m, 1H), 4.40(q, 1H, J=6.9Hz), 3.95-3.87(m, 1H), 3.59-3.52(m, 1H), 1.91-1.55(m, 6H), and 1.48(d,3H, J=6.9 Hz)

EXAMPLE 5 Synthesis of(3R)-3-(tert-butyldimethylsilyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone

Tetrahydrofuran (15 mL) was added to triazole sodium acetate (1.02 g,6.87 mmol) and anhydrous magnesium chloride (1.31 g, 13.7 mmol), and themixture was stirred at room temperature for two hours. A solution (15.1mL) of tetrahydrofuran containing tert-butyl magnesium chloride (0.91 M)was added to the mixture, and the mixture was heated at 40° C. to 45° C.Subsequently, a solution of tetrahydrofuran (3 mL) containing methyl(2R)-2-(tert-butyldimethylsilyloxy)propionate (1.00 g 4.58 mmol) wasadded dropwise to the mixture at 40° C. to 45° C. for one hour. Themixture was then stirred at 40° C. to 45° C. for four hours. Sulfuricacid (10%) was added to the reaction mixture so that the pH of thereaction mixture was controlled in the range of 2 to 4. The targetcompound was extracted with toluene (20 mL). The extracted solution waswashed with water, and was then dried with anhydrous magnesium sulfate.The drying agent was filtered, and the filtrate was concentrated underreduced pressure. The resultant crude product was purified by silica gelcolumn chromatography (equivalent to Merck C-300, 15 g, hexane:ethylacetate=3:1 to 2:1 to 1:1) to recover the target compound (1.09 g, 82%),which was a transparent and colorless syrup.

¹H-N.M.R. (270 MHz, CDCl₃): δ=8.14(s, 1H), 7.98(s, 1H), 5.42(d, 1H,J=19.1 Hz), 5.22(d, 1H, J=19.1 Hz), 4.39(q, 1H, J=6.9 Hz), 1.40(d, 3H,J=6.9 Hz), 0.97(s, 9H), and 0.16(s, 6H)

-   Optical purity by a chiral HPLC area method: 99% ee Analytical    conditions/DAICEL CHIRALPAK AD, Eluent composition:    hexane:2-propanol:diethylamine=90:10:0.1, Detection method: UV 220    nm

EXAMPLE 6 Synthesis of(3R)-3-(3,4,5,6-tetrahydro-2H-pyran-1-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone

The target compound (2.15 g, 45%), which was a transparent and colorlesssyrup and was a mixture of two diastereomers derived from the THP group,was recovered as in Example 1, except methyl(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-1-yloxy) propionate (3.77 g, 20mmol) was used.

THP group-derived diastereomer A; ¹H-N.M.R. (270 MHz, CDCl₃): δ=8.11(s,1H), 7.97(s, 1H), 5.36(d, 1H, J=8.8 Hz), 5.22(d, 1H, J=8.8 Hz),4.73-4.70(m, 1H), 4.40(q, 1H, J=6.9 Hz), 3.95-3.87(m, 1H), 3.59-3.52(m,1H), 1.91-1.55(m, 6H), and 1.48(d, 3H, J=6.9 Hz)

THP group-derived diastereomer B; ¹H-N.M.R. (270 MHz, CDCl₃): δ=8.11(s,1H), 7.96(s, 1H), 5.50(d, 1H, J=8.8 Hz), 5.32(d, 1H, J=8.8 Hz),4.57-4.54(m, 1H), 4.24(q, 1H, J=6.9 Hz), 3.95-3.89(m, 1H), 3.52-3.42(m,1H), 1.89-1.84(m, 2H), 1.57-1.54(m, 4H), and 1.39(d, 3H, J=6.9 Hz)

EXAMPLE 7 Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanoland (2S,3R)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

2,4-Difluorobromobenzene (202 mg, 1.05 mmol) was dissolved in ether (4mL). A solution of hexane (0.66 mL, 1.05 mmol) containing n-butyllithium(1.59 M) was added dropwise to the mixture at −70° C. to −65° C., andthe mixture was stirred for 30 minutes. The resultant mixture ishereinafter referred to as Mixture A. Anhydrous cerium chloride (258 mg,1.05 mmol) was dried at 140° C. for one hour under reduced pressure, andwas then cooled to room temperature. Tetrahydrofuran (3 mL) was added tothe anhydrous cerium chloride, and was subsequently subjected toultrasonic treatment for 30 minutes. The resultant suspension ishereinafter referred to as Suspension B. Suspension B was added dropwiseto Mixture A, which was cooled at a temperature in the range of −70° C.to −65° C. Subsequently, a solution of ether (2 mL) containing(3R)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone (70 mg,0.35 mmol) was added dropwise to the mixture at −70° C. to −65° C. Themixture was stirred at this temperature for 30 minutes. The temperatureof the mixture was then increased to room temperature. Ethyl acetate (10mL) and water (10 mL) were added to the reaction mixture and an organiclayer was separated. The organic layer was washed with a saturatedsaline solution (5 mL) and was then dried with anhydrous magnesiumsulfate. The drying agent was filtered and the filtrate was concentratedunder reduced pressure. The resultant product was purified bypreparative silica gel thin layer chromatography (Merck, 20 cm×20 cm×2mm, developing solution: pure ethyl acetate) to recover the targetcompound (38 mg, 35%), which was a mixture of diastereomers. Thecompound was a transparent and colorless syrup. The ratio of thediastereomers was (2R, 3R):(2S, 3R)=6:1. The ratio of the diastereomerswas determined by derivatives, as will be described in Example 18, inwhich the methoxymethyl group was deprotected.

(2R, 3R)-Diastereomer; ¹H-N.M.R. (270 MHz, CDCl₃): δ=7.89(s, 1H),7.73(s, 1H), 7.48-7.38(m, 1H), 6.79-6.71(m, 2H), 4.91-4.72(m, 4H),4.29(q, 1H, J=6.6 Hz), 4.13(s, 1H), 3.46(s, 3H), and 1.03(d, 3H, J=6.6Hz)

(2S, 3R)-Diastereomer; ¹H-N.M.R. (270 MHz, CDCl₃): δ=8.02(s, 1H),7.72(s, 1H), 7.49-7.40(m, 1H), 6.79-6.69(m, 2H), 4.99(d, 1H, J=13.8 Hz),4.59(d, 1H, J=7.0 Hz), 4.48(d, 1H, J=13.8 Hz), 4.42(d, 1H, J=7.0 Hz),4.41(s, 1H), 4.15(q, 1H, J=6.3 Hz), 3.08(s, 3H), and 1.28(d, 3H, J=6.3Hz)

EXAMPLE 8 Synthesis of (2R,3R)-3-(benzyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanoland (2S,3R)-3-(benzyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Magnesium (6.0 g, 46 mmol) was dispersed in tetrahydrofuran. (120 mL) ina nitrogen atmosphere. Iodine (5 mg) was-added and the mixture wasstirred. A solution of tetrahydrofuran (120 mL) containing2,4-difluorobromobenzene (48 g, 248 mmol) was added dropwise to themixture so that the internal temperature was controlled 30° C. to 35° C.The resultant mixture is hereinafter referred to as Grignard reagent A.Anhydrous cerium chloride (10 g, 40.8 mmol) was dried at 130° C. for onehour under reduced pressure, and was then cooled to room temperature.Tetrahydrofuran (40 mL) was added to the anhydrous cerium chloride in anitrogen atmosphere, and the resultant suspension was subsequentlysubjected to ultrasonic treatment for 30 minutes. The suspension ishereinafter referred to as Suspension B. Subsequently, a solution oftetrahydrofuran (10 mL) containing(3R)-3-(benzyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone (5.0 mg, 20.4mmol) was added to Suspension B, and the mixture was further subjectedto ultrasonic treatment for 30 minutes. Tetrahydrofuran (4 mL) was addedto the resultant Suspension B, and then the temperature of thesuspension was kept at 0° C. to −5° C. Grignard reagent A (24 mL, 24mmol) was added dropwise to the suspension. Subsequently, the mixturewas further stirred for 12 hours. The reaction mixture was cooled on iceand hydrochloric acid (1 N, 200 mL) was added dropwise to the mixture.Ethyl acetate (400 mL) was added to the mixture to extract the targetcompound. Thus, an organic layer was separated. The organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate(400 mL), and subsequently washed with a saturated saline solution (400mL). The organic layer was then dried with magnesium sulfate. The dryingagent was filtered and the filtrate was concentrated to produce an oilyproduct (10 g). The product was purified by silica gel columnchromatography (equivalent to Merck C-300, 10 g, hexane:ethylacetate=2:1 to 1:1) to recover the target compound (900 mg, 12%). Thecompound was a transparent and colorless syrup. The ratio of thediastereomers was (2R, 3R):(2S, 3R)=1:14. The ratio of the diastereomerswas determined by derivatives, as will be described in Example 14, inwhich the benzyl group was deprotected.

(2R, 3R)-Diastereomer; ¹H-N.M.R. (400 MHz, CDCl₃): δ=7.85(s, 1H),7.67(s, 1H), 7.42-7.30(m, 6H), 6.76-6.68(m, 2H), 4.77(d, 1H, J=11.5 Hz),4.72(s, 2H), 4.51(d, 1H, J=11.5 Hz), 4.15(q, 1H, J=6.3 Hz), 4.02(s, 1H),and 1.04(d, 1H, J=6.3 Hz)

(2S, 3R)-Diastereomer; ¹H-N.M.R. (400 MHz, CDCl₃): δ=7.99(s, 1H),7.72(s, 1H), 7.49-7.43(m, 1H), 7.29-7.26(m, 3H), 7.10-7.08(m, 2H),6.80-6.75(m, 1H), 6.71-6.65(m, 1H), 4.96(d, 1H, J=14.5 Hz), 4.53(d, 1H,J=10.4 Hz), 4.45(d, 1H, J=14.5 Hz), 4.36(s, 1H), 4.27(d, 1H, J=10.4 Hz),3.90(q, 1H, J=6.1 Hz), and 1.25(d, 3H, J=6.1 Hz)

The above mixture of diastereomers, which was a transparent andcolorless syrup, was crystallized by using hexane and ethyl acetate asthe crystallization solvent. White crystals (40 g, 10%) of the (2R,3S)-diastereomer were preferentially recovered. Melting point: 103° C.to 105° C., Diastereomeric excess: 98% de The diastereomeric excess wasdetermined by derivatives, as will be described in Example 14, in whichthe benzyl group was deprotected.

EXAMPLE 9 Synthesis of (2S,3S)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanoland (2R,3S)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

2,4-Difluorobromobenzene (139 mg, 0.72 mmol) was dissolved intetrahydrofuran (4 mL). A solution of hexane (0.45 mL, 0.72 mmol)containing n-butyllithium (1.59 M) was added dropwise to the mixture at−70° C. to −65° C., and the mixture was stirred for 30 minutes.Subsequently, a solution of ether (1 mL) containing(3S)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone (47.5 mg,0.24 mmol) was added dropwise to the mixture at −70° C. to −65° C. Themixture was stirred at this temperature for 30 minutes. The temperatureof the mixture was then increased to room temperature. Ethyl acetate (10mL) and water (10 mL) were added to the reaction mixture and an organiclayer was separated. The organic layer was washed with a saturatedsaline solution (5 mL) and was then dried with anhydrous magnesiumsulfate. The drying agent was filtered and the filtrate was concentratedunder reduced pressure. The resultant product was purified bypreparative silica gel thin layer chromatography (Merck, 20 cm×20 cm×2mm, developing solution: pure ethyl acetate) to recover the targetcompound (15 mg, 20%), which was a mixture of diastereomers. Thecompound was a transparent and colorless syrup. The ratio of thediastereomers was (2S, 3S):(2R, 3S)=5:1. The ratio of the diastereomerswas determined by derivatives, as will be described in Example 18, inwhich the methoxymethyl group was deprotected. The values of thephysical properties corresponded with those in Example 7.

EXAMPLE 10 Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(triphenylmethyloxy)-2-butanoland (2S,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(triphenylmethyloxy)-2-butanol

The target compound (200 mg, 10%), which was a mixture of diastereomers,was recovered as in Example 7, except(3R)-1-(1H-1,2,4-triazol-1-yl)-3-(triphenylmethyloxy)-2-butanone (1.55g) was used instead of(3R)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone. Thetarget compound was a light yellow syrup. The ratio of the diastereomerswas (2R, 3R):(2S, 3R)=4.3:1. The ratio of the diastereomers wasdetermined by derivatives, as will be described in Example 17, in whichthe trityl group was deprotected.

(2R, 3R)-Diastereomer; ¹H-N.M.R. (270 MHz, CDCl₃): δ=8.10-7.08(m, 18H),6.79-6.49(m, 2H), 4.47(d, 1H, J=15 Hz), 4.40-4.20(m, 2H), 3.79(q, 1H,J=6.9 Hz), and 0.80(d, 3H, J=6.9 Hz)

(2S, 3R)-Diastereomer; ¹H-N.M.R. (270 MHz, CDCl₃): δ=8.10-7.08(m, 18H),6.79-6.49(m, 2H), 4.58(d, 1H, J=15 Hz), 4.46(s, 1H), 4.30-4.20(m, 1H),3.71(q, 1H, J=6.9 Hz), and 1.00(d, 3H, J=6.9 Hz)

EXAMPLE 11 Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanoland (2S,3R)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

The target compound (28 mg, 37%), which was a mixture of diastereomers,was recovered as in Example 8, except(3R)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone (48 mg,0.35 mmol) was used instead of(3R)-3-(benzyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone. The targetcompound was a transparent and colorless syrup. The ratio of thediastereomers was (2R, 3R):(2S, 3R)=1:8. The ratio of the diastereomerswas determined by derivatives, as will be described in Example 18, inwhich the methoxymethyl group was deprotected. The values of thephysical properties corresponded with those in Example 9.

EXAMPLE 12 Synthesis of (2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanoland (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Magnesium (5.96 g, 245 mmol) was dispersed in tetrahydrofuran (175 g),and iodine (5 mg) was added to the dispersion liquid. A solution oftetrahydrofuran (60 g) containing 2,4-difluorobromobenzene (47.3 g, 245mmol) was added dropwise to the mixture at room temperature to prepare aGrignard reagent.(3R)-3-(Tert-butyldimethylsilyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone(20 g, 74.2 mmol) and anhydrous magnesium chloride (21.2 g, 223 mmol)were suspended in tetrahydrofuran (100 g), and the suspension was cooledto −35° C. The above Grignard reagent was added dropwise to thesuspension for 45 minutes. Subsequently, the suspension was stirred for15 minutes and then hydrochloric acid (1 N, 245 mL) was added to stopthe reaction. Toluene (180 mL) was added to the mixture to extract thetarget compound. Thus, an organic layer was separated. The organic layerwas washed with water (90 mL). The organic layer was then dried withanhydrous magnesium sulfate. The drying agent was filtered and thefiltrate was concentrated under reduced pressure. The product waspurified by silica gel column chromatography (equivalent to Merck C-300,300 g, hexane:ethyl acetate=3:1 to 3:2 to 1:1) to recover the targetcompound (21.9 g, 77%), which was a mixture of diastereomers. Thecompound was a light yellow syrup. The ratio of the diastereomers was(2R, 3R):(2S, 3R)=23:1. The ratio of the diastereomers was determined byderivatives, as will be described in Example 15, in which thetert-butyldimethylsilyl group was deprotected.

(2R, 3R)-Diastereomer; ¹H-N.M.R. (270 MHz, CDCl₃): δ=7.94(s, 1H),7.68(s, 1H), 7.42-7.33(m, 1H), 6.80-6.71(m, 2H), 4.82(d, 1H, J=13.8 Hz),4.55(d, 1H, J=13.8 Hz), 4.45-4.42(m, 1H), 3.77(s, 1H), 0.98(d, 3H, J=6.0Hz), 0.98(s, 9H), and 0.18(s, 6H)

(2S, 3R)-Diastereomer; ¹H-N.M.R. (270 MHz, CDCl₃): δ=8.17(s, 1H),7.80(s, 1H), 7.42-7.33(m, 1H), 6.80-6.71(m, 2H), 4.96(d, 1H, J=13.8 Hz),4.57(d, 1H, J=13.8 Hz), 4.35-4.25(m, 1H), 3.77(s, 1H), 1.22(d, 3H, J=6.0Hz), 0.90(s, 9H), and 0.09(s, 6H)

The above mixture of diastereomers, which was a light yellow syrup, wascrystallized by using hexane as the crystallization solvent. Whitecrystals (17.3 g, 61%) of the (2R, 3R)-diastereomer were preferentiallyrecovered. Melting point: 106° C. to 107° C., Diastereomeric excess:99.5% de The diastereomeric excess was determined by derivatives, aswill be described in Example 15, in which the tert-butyldimethylsilylgroup was deprotected. Optical purity by a chiral HPLC area method: 99%ee

Analytical conditions/DAICEL CHIRALPAK AD, Eluent composition:hexane:2-propanol:diethylamine=90:10:0.1, Detection method: UV 254 nm

EXAMPLE 13 Synthesis of (2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanoland (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

The target compound (36 mg, 46%), which was a mixture of diastereomers,was recovered as in Example 7, except(3R)-3-(tert-butyldimethylsilyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone(55 mg, 0.204 mmol) was used instead of(3R)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanone. Thetarget compound was a light yellow syrup. The ratio of the diastereomerswas (2R, 3R):(2S, 3R)=6:1.

The ratio of the diastereomers was determined by derivatives, as will bedescribed in Example 15, in which the tert-butyldimethylsilyl group wasdeprotected. The values of the physical properties corresponded withthose in Example 12.

EXAMPLE 14 Synthesis of (2S,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol

The (2S,3R)-3-(benzyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(719 g, 2 mmol) synthesized in Example 8 was dissolved in methanol (30mL). Fifty percent-hydrated 10%-palladium-carbon (0.3 g) was added tothe solution and the mixture was stirred in an autoclave at 1.0 MPa ofhydrogen initial pressure, at 50° C. for eight hours. The catalyst wasfiltered from the reaction solution and the filtrate was concentratedunder reduced pressure to recover the target compound (480 mg, 89%). Thecompound was a white amorphous solid. Diastereomeric excess: 98% de

Analytical conditions/YMC-PACK ODS A-303, Eluent composition:methanol:water:acetic acid=70:30:0.2, Detection method: UV 254 nm

¹H-N.M.R. (270 MHz, CDCl₃): δ=8.04(s, 1H), 7.77(s, 1H), 7.58-7.52(m,1H), 6.83-6.69(m, 2H), 5.03(d, 1H, J=14 Hz), 5.02(s, 1H), 4.56(d, 1H,J=14 Hz), 4.03-3.97(m, 1H), 2.59(d, 1H, J=5.3 Hz), and 1.26(d, 3H, J=6.6Hz)

EXAMPLE 15 Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol

The (2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(2.0 g, 5.22 mmol) synthesized in Example 12 was dissolved intetrahydrofuran (20 g). Tetra-n-butyl-ammonium fluoride (2.05 g, 7.83mmol) was added to the solution and the mixture was stirred at roomtemperature for 30 minutes. Water (20 g) and ethyl acetate (40 g) wereadded to the reaction mixture and the mixture was stirred for 10minutes. Subsequently, an organic layer was separated. The organic layerwas dried with anhydrous magnesium sulfate. The drying agent wasfiltered and the filtrate was concentrated under reduced pressure. Theresultant light yellow syrup was crystallized with toluene to recoverwhite crystals of the target compound (1.31 g, 94%). Melting point: 116°C. to 117° C., Optical purity: 99% ee, Diastereomeric excess: 99.5% de

Analytical conditions/YMC-PACK ODS A-303, Eluent composition:methanol:water:acetic acid=70:30:0.2, Detection method: UV 254 nm

¹H-N.M.R. (270 MHz, CDCl₃): δ=7.84(s, 1H), 7.82(s, 1H), 7.46-7.37(m,1H), 6.80-6.72(m, 2H), 4.87-4.77(m, 3H), 4.36-4.29(m, 1H), 2.63(d, 1H,J=9.2 Hz), and 0.97(d, 3H, J=6.5 Hz)

EXAMPLE 16 Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol

The (2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(12.2 g) synthesized in Example 12 was dissolved in methanol (41 mL).Hydrochloric acid (3 N, 21 g) was added to the solution and the mixturewas stirred at 50° C. for four hours. Toluene (120 g) was added to thereaction mixture and was then stirred. Subsequently, an aqueous layerwas separated. An aqueous solution (2 N, 41 g) of sodium hydroxide wasadded to the aqueous layer so that the pH of the mixture was controlledto be 9. The target compound was extracted with ethyl acetate (120 mL).The extracted organic layer was dried with anhydrous magnesium sulfate.The drying agent was filtered, and the filtrate was concentrated underreduced pressure. The resultant light yellow syrup was crystallized withtoluene to recover-white crystals of the target compound (7.9 g, 92%).The values of the physical properties corresponded with those in Example15. Diastereomeric excess: 99.5% de

EXAMPLE 17 Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol and(2S, 3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol

The mixture (225 mg, 0.5 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanoland (2S, 3R) (2R,3R)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanolsynthesized in Example 7 was treated as in Example 16 to recover thetarget compound (121 mg, 90%), which was a mixture of diastereomers. Theratio of the diastereomers was (2R, 3R):(2S, 3R)=4.3:1.

Analytical conditions/YMC-PACK ODS A-303, Eluent composition:methanol:water:acetic acid=70:30:0.2, Detection method: UV 254 nm

The spectral data of ¹H-N.M.R. corresponded with those in Examples 15and 16.

EXAMPLE 18 Synthesis of (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol and(2S, 3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol

The mixture (38 mg, 0.121 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanoland (2S,3R)-2-(2,4-difluorophenyl)-3-(methoxymethyloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanolsynthesized in Example 10 was treated as in Example 16 to recover thetarget compound (28 mg, 85%), which was a mixture of diastereomers. Theratio of the diastereomers was (2R, 3R):(2S, 3R)=6:1.

Analytical conditions/YMC-PACK ODS A-303, Eluent composition:methanol:water:acetic acid=70:30:0.2, Detection method: UV 254 nm

The spectral data of ¹H-N.M.R. corresponded with those in Examples 15and 16.

INDUSTRIAL APPLICABILITY

The present invention provides a new method for producing a new,optically active azole alkyl ketone derivative and a new, opticallyactive azole-methyl alcohol derivative, which are significantlyimportant intermediates of medicines and agricultural chemicals.Furthermore, the present invention provides a stable method forinexpensively producing an optically active2-phenyl-2,3,-dihydroxypropyl azole derivative by simple steps.

1. A method for producing an optically active azole-methyl alcoholderivative represented by general formula (5):

(wherein R1 represents a substituted or unsubstituted alkyl group; R2represents an ether protective group, an acetal protective group, or asilyl protective group, which is a protective group for a hydroxylgroup; each of R5 and R6 independently represents a halogen atom;symbol * represents an asymmetric carbon having an R configuration or anS configuration; and Y represents a carbon atom or a nitrogen atom) themethod comprising: allowing an optically active azole-methyl ketonederivative represented by general formula (3):

(wherein R1, R2, Y, and symbol * are as defined above) todiastereoselectively react with a phenyl metallic reagent represented bygeneral formula (4):

(wherein R5 and R6 are as defined above; A represents Li, MgX, ZnX,TiX₃, Ti(OR7)₃, CuX, or CuLi, {wherein X represents a halogen atom, andR7 represents a substituted or unsubstituted alkyl group}).
 2. Themethod according to claim 1 wherein R1 is a methyl group, and each of R5and R6 is a fluorine or chlorine atom.
 3. A method according to claim 1,wherein the optically active azole-methyl ketone derivative representedby general formula (3) is allowed to anti-selectively with the phenylmetallic reagent represented by general formula (4).
 4. The methodaccording to claim 3 wherein R1 is a methyl group, and each of R5 and R6is a fluorine or chlorine atom.
 5. The method according to claim 1,wherein the optically active azole-methyl ketone derivative representedby general formula (3) is allowed to syn-selectively react with thephenyl metallic reagent represented by general formula (4).
 6. Themethod according to claim 5 wherein R1 is a methyl group, and each of R5and R6 is a fluorine or chlorine atom.
 7. An optically activeazole-methyl alcohol derivative represented by general formula (5):

(wherein R1 represents a substituted or unsubstituted alkyl group; R2 isa silyl protective group; each of R5 and R6 independently represents ahalogen atom; symbol * represents an asymmetric carbon having an Rconfiguration or an S configuration; and Y represents a carbon atom or anitrogen atom.
 8. The optically active azole-methyl alcohol derivativeaccording to claim 7, wherein R1 is a methyl group.
 9. The opticallyactive azole-methyl alcohol derivative according to claim 7, whereineach of R5 and R6 is a flourine or chlorine atom.
 10. The opticallyactive azole-methyl alcohol derivative according to claim 7, wherein Yis a nitrogen atom.
 11. The optically active azole-methyl alcholderivative according to claim 7, wherein R2 is one selected from thegroup consisting of trimethylsilyl, triethylsilyl,tert-butyldimethylsilyl, and tert-butyldiphenylsilyl groups.
 12. Themethod according to claim 1, wherein R2 is one selected from the groupconsisting of methyl, ethyl, tert-butyl, octyl, allyl, benzyl,p-methoxybenzyl, fluorenyl, trityl, benzhydryl, methoxymethyl,ethoxyethyl, methoxyethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl,trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, andtert-butyldiphenylsilyl groups.
 13. The method according to claim 2,wherein R2 is one selected from the group consisting of methyl, ethyl,tert-butyl, octyl, allyl, benzyl, p-methoxybenzyl, fluorenyl, trityl,benzhydryl, methoxymethyl, ethoxyethyl, methoxyethoxymethyl,tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl,tert-butyldimethylsilyl, and tert-butyldiphenylsilyl groups.
 14. Themethod according to claim 3, wherein R2 is one selected from the groupconsisting of methyl, ethyl, tert-butyl, octyl, allyl, benzyl,p-methoxybenzyl, fluorenyl, trityl, benzhydryl, methoxymethyl,ethoxyethyl, methoxyethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl,trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, andtert-butyldiphenylsilyl groups.
 15. The method according to claim 5,wherein R2 is one selected from the group consisting of methyl, ethyl,tert-butyl, octyl, allyl, benzyl, p-methoxybenzyl, fluorenyl, trityl,benzhydryl, methoxymethyl, ethoxyethyl, methoxyethoxymethyl,tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl,tert-butyldimethylsilyl, and tert-butyldiphenylsilyl groups.
 16. Themethod according to claim 1, wherein the azole-methyl ketone derivativerepresented by general formula (3) is obtained by the method comprising:allowing an α-hydroxycarboxylic acid derivative represented by generalformula (1):

(wherein R1, R2, and symbol * are as defined in claim 1 and R3represents a hydroxyl group, a halogen atom, a substituted orunsubstituted acyl group, a substituted or unsubstituted carbonategroup, a substituted or unsubstituted alkyloxy group, a substituted orunsubstituted aralkyloxy group, a substituted or unsubstituted phenoxygroup, or a substituted or unsubstituted amino group) to react with anazole acetic acid derivative represented by general formula (2):

(wherein R4 represents a hydrogen atom, a substituted or unsubstitutedalkyl group, an alkali metal, or an alkaline earth metal salt; and Y isas defined in claim 1) under a basic condition.
 17. The method accordingto claim 16 wherein R1 is a methyl group.
 18. A method for producing anoptically active 2-phenyl-2,3-dihydroxypropyl azole derivativerepresented by general formula (6):

(wherein R1, R5, R6 and symbol * represents the same as defined in claim1), said method comprising: selectively deprotecting the protectivegroup R2 for a hydroxyl group of the optically active azole-methylalcohol derivative represented by general formula (5) obtained by themethod as claimed in claims 1.